tbuckley/cabot-search huggingface dataset:
IMMU-40. DECITABINE PRIMES GLIOBLASTOMA TO NY-ESO-1 SPECIFIC T-CELL CYTOLYSIS VIA DNA DEMETHYLATION OF NY-ESO-1, CANCER-TESTIS ANTIGENS, AND PRO-INFLAMMATORY SIGNATURES
Authors: Thomas Lai, Lu Sun, Janet Treger, Tie Li, Kevin Li, Terry Prins, Albert Lai, Robert Prins, Richard Everson
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Previous work has shown that the DNA hypomethylating agent, Decitabine (DAC), can improve the immunogenicity of Glioblastoma (GBM) for immuno-therapeutic targeting through the upregulation of cancer testis antigens (CTA). Specifically, our group has published preclinical proof of principle that DAC upregulates NY-ESO-1, a well-studied and highly immunogenic CTA, in GBM for targeting by systemic adoptive T-cell therapy. However, the exact mechanisms by which this DAC-induced immunogenic enhancement occurs in GBM remains to be elucidated. We hypothesize that hypomethylating agents like DAC enable targeted immune therapy to overcome low immunogenicity in GBM cells via CpG demethylation of antigens and subsequent upregulation of inflammatory and antigen presentation gene signatures. METHODS We induced NY-ESO-1 expression in vitro in immortalized GBM lines and primary gliomaspheres using DAC and investigated the response of DAC-treatment using targeted bisulfite sequencing and quantitative real-time PCR. To functionally assess for specific immune killing of DAC treated GBM cells, we co-cultured DAC-treated cell lines with T-cells transduced to express a NY-ESO-1 specific T-cell receptor. Lastly, we performed probe-based methylation array and bulk RNA sequencing to interrogate global transcriptomic and epigenomic changes resulting from DAC treatment. RESULTS Sustained exposure to low dose (0.5 uM – 1 uM) DAC in immortalized and primary cell lines resulted in time-dependent demethylation of the CpG island of NY-ESO-1 and the subsequent robust increase in mRNA expression. Upregulation of NY-ESO-1 rendered specific T cell recognition and lysis of immortalized and primary cell lines. DAC upregulated other pro-inflammatory and immuno-modulatory signatures via CpG demethylation to enhance T-cell mediated targeted cytolysis of GBM. CONCLUSION Hypomethylating agents like DAC upregulate immunogenic signatures in primary and immortalized GBM cells, rendering them susceptible to antigen specific T-cell targeting. These pleiotropic effects demonstrate strong preclinical rationale for use of DAC to sensitize GBM for targeting by immune therapies.
RADT-17. SINGLE INSTITUTION REVIEW OF OUTCOMES FOLLOWING STEREOTACTIC RADIOSURGERY FOR SIX TO EIGHTEEN BRAIN METASTASES: INTRACRANIAL FAILURE RATES AND NEED FOR FURTHER CRANIAL RADIOTHERAPY
Authors: Sophie Lynch, Kazumi Chia, Vishal Manik, Lucy Brazil, Samantha Forner, Jeyaanth Venkatasai, Sheila Hassan, Yasmin Akhtar, Kirsty Blythe, Omar Al-Salihi
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND A single centre retrospective review of outcomes following linear accelerator - based stereotactic radiosurgery (SRS) for patients with 6 to 18 brain metastases was conducted. METHODS Patients receiving SRS to multiple metastatic sites were identified from our institutional database and subsequently stratified into those with 6-9 metastases (group 1) and 10 or more metastases (group 2). RESULTS 45 patients were evaluated in total with a mean number of metastases of 7 for group 1 and 14 for group 2. Mean total GTV volumes for each SRS treatment were 1.92cc (group 1) and 2.70cc (group 2). Median overall survival was 8 months for group 1 (0 -51 months) and 7 months (3-36 months) for group 2 . Following SRS, median time to intracranial progression was 3 months for both groups, occurring in 59% and 64% of group 1 and group 2 patients respectively. Following relapse, more patients in group 2 received whole brain/posterior fossa radiotherapy rather than SRS when compared with those in group 1 (80% vs 40%). The majority of patients surviving more than 1 year following SRS for ≥6 brain metastases had a targetable mutation (defined as any of ALK/EGFR/ROS1/BRAF mutation, ER+, HER 2+, PDL1 expression ≥ 1) in their primary tumour; 75% of group 1 and 100% of group 2. CONCLUSIONS Although this study represents small patient numbers, we show that long term survival can be achieved for some patients following SRS for more than 5 brain metastases. However, many patients with more than 10 brain metastases develop intracranial relapse shortly after SRS and require whole brain/posterior fossa radiotherapy, indicating these patients are less likely to benefit from SRS. The presence of a targetable mutation in the primary tumour may indicate a better outcome following SRS for more than 5 brain metastases and warrants further investigation.
EPCO-20. DYNAMICS OF TUMOR GENOME SHAPING AND CLINICAL RESPONSE IN GLIOBLASTOMAS UNDER IMMUNE CHECKPOINT INHIBITORS
Authors: Seung-Won Choi, Raul Rabadan, Fabio Iwamoto, Peter Pan
Journal: Neuro-Oncology (2023)

Abstract Immune checkpoint inhibitors (ICI) have shown remarkable success in several tumor types; however, this success has not been common in glioblastomas (GBMs). Given the immune-suppressive tumor microenvironment, the timing when to apply ICI may be a determining factor for clinical success. With this hypothesis, we compiled a longitudinal cohort of GBMs treated with different ICI schemes and a control cohort (upfront ICI (n=16), recurrent ICI (n=23), and control cohort by standard of care (n=33)). We investigated the genomic correlates to clinical response. Neither ICI itself nor different timing strategies failed to show a survival benefit for GBMs. However, the upfront-ICI cohort had more long-term survivors (overall survival &amp;gt;= 36 months) than the recurrent-ICI cohort (37.5% (n=6/16) vs. 26.1% (n=6/23)). Genomic analysis revealed that alterations in the PI3K-pathway or TP53 were associated with a poor response to ICI, while BRAF mutation was related to a favorable response. Interestingly, only TP53 alteration was associated with a worse prognosis in GBMs treated with upfront ICI. Tumor mutational burden (TMB) or the amount of neo-antigens failed to show any correlation with the response to ICI. However, ICI-treated GBMs experienced divergent evolution regarding the TMB, while GBMs treated by standard of care only exhibited unidirectional change. We also explored the immunogenomic shifts following different treatment modalities. ICI-treated GBMs showed more variable changes in both HLA alleles and neo-antigen burden (p-value=0.41 &amp; 0.008, respectively). Among the upfront-ICI cohort, GBMs with a better response showed an increased neo-antigen burden upon recurrence (p-value=0.03), suggesting the selection of fitting clones during therapy. Collectively, we observed that that GBMs experienced distinct evolutions under different treatment schemes. The vulnerability of GBMs to ICI should be considered in the context of tumors’ capability to dynamically shape the tumor genome to fit into therapeutic pressure.
EXTH-08. IMMUNOTHERAPEUTIC TARGETING OF FIBROBLAST ACTIVATION PROTEIN (FAP) IN TREATMENT REFRACTORY GLIOBLASTOMA USING NOVEL CAR-T CELL THERAPY
Authors: Nazanin Tatari, Hayget Mohamed Seid Hedad, Andreas Zingg, Ewelina M Bartoszek, Viviane J Tschan, Timo Schenker, Marie-Françoise Ritz, Petar Miletic, Chitra Venugopal, Manina M Etter, Sheila K Singh, Heinz Läubli, Gregor Hutter
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM), the most common malignant primary adult brain tumor, is characterized by extensive cellular and genetic heterogeneity. The standard of care therapy and clinical trials have not been successful in improving patients’ survival which underscores an urgent need for developing new effective therapies. In silico and in vitro analysis have revealed high level of Fibroblast Activation Protein (FAP) expression in GBM tissue by multiple cell populations including endothelial cells, fibroblasts, stromal and tumor cells, but not normal brain tissue, making FAP a safe and suitable therapeutic target. As chimeric antigen receptor (CAR) expressing T cells have shown promising results against multiple cancers, we aimed to target FAP in GBM by FAP specific CAR-T cells generated using a novel GMP-ready FAP-CAR construct produced based on a virus-free CAR gene transfer using advanced sleeping beauty transposon technology and pre-clinically test their anti-tumor efficacy. Our data revealed that co-culturing CAR-T cells with FAP+ GBM cells (U87) resulted in increased surface expression of T-cell activation markers. Moreover, FAP CAR-T mediated cytotoxicity against FAP+ GBM cells was also observed in the co-culture of GBM and CAR-T cells. For further validation, the effect of FAP CAR-T cells will be tested on patient-derived GBM organoids. The in vivo efficacy of FAP CAR-T cells is currently under investigation and we anticipate that the treatment of GBM tumor-bearing mice with FAP CAR-Ts results in extended survival and tumor burden reduction. These rigorously obtained data show high level of efficacy for FAP-specific CAR-T cells against GBM suggesting that clinical development of this therapeutic modality can provide a novel therapeutic strategy for GBM patients. Therefore, upon successful completion of the preclinical study, we plan to conduct a phase I dose-escalation trial of autologous FAP-CAR T cells for patients with recurrent Glioblastoma.
BIOM-11. THE ROLE OF INSULIN-LIKE GROWTH FACTOR 2 BINDING PROTEIN 3 (IGF2BP3) AS A DRIVER OF TUMORIGENESIS IN GLIOBLASTOMA
Authors: Jocelyn Chow, Alexander Chen, Se-yeong Oh, Elizabeth Young, Nathaniel Boyd, Renee Read
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor with a poor median survival of fifteen months after diagnosis. GBM accounts for half of malignant and fifteen percent of all primary brain tumors diagnosed in adults. To promote targeted therapy, there are ongoing efforts to understand GBM at a molecular level. This involves characterization of these tumors via their transcriptional and mutational profile. Recent studies indicate aberrations in receptor tyrosine kinase (RTKs), including EGFR and PDGFRA, and the Pi-3 kinase (PI3K) signaling pathways are major drivers of tumorigenesis in GBM. Using a proteomics approach to locate downstream targets of these pathways, we identified IGF2 Binding Protein 3 (IGF2BP3), which is an RNA binding protein, as a downstream effector of aberrant RTK-PI3K signaling in gliomagenesis. Our subsequent follow-up studies indicate that IGF2BP3, which is overexpressed in RTK mutant human GBMs, drives survival and proliferation of RTK-PI3K-dependent human GBM cells. To understand how IGF2BP3 functions to promote RTK-PI3K driven tumorigenesis, we used cultured human GBM cells and in GBM xenograft models to test the effects of loss of IGF2BP3 function in tumorous glia as well as normal glia. Our results indicate that IGF2BP3 activity is essential for self-renewal and maintenance of neural stem-cell like features of GBM tumor cells, but dispensable for the growth of normal glia. Currently, we are using genetic approaches to identify and validate RNA targets of IGF2BP3 function in tumor cells and to understand how these targets are specifically regulated by RTK-PI3K-dependent signaling in glioma. Overall, our data suggests that IGF2BP3 may play a role in promoting GBM tumorigenesis and our future directions aim to reveal an important tumor-specific RNA target signaling pathway for consideration in potential therapeutics.
BIOM-28. PROGNOSTIC BIOMARKERS IN GLIOBLASTOMA PATIENTS TREATED WITH TEMOZOLOMIDE
Authors: Shuodan Zhang, Nadia Mcmillan, Matthew McGuinness, Stephen Trudeau, Erik Uhlmann
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE Identifying blood biomarkers that predict favorable outcomes for patients with glioblastoma treated with temozolomide (TMZ). BACKGROUND Glioblastoma is the most aggressive primary brain tumor. The standard of care is maximum safe resection, then radiation plus oral TMZ, followed by six months of cyclic oral TMZ. Previous studies have revealed that TMZ-induced myelosuppression is associated with improved overall survival. METHODS Adults with glioblastoma who completed radiation therapy and received temozolomide for at least 6-months at Beth Israel Deaconess Medical Center between 2018-2021 were identified. Baseline and nadir white blood cell count, absolute neutrophil count, absolute lymphocyte count, red blood cells, and platelets were collected retrospectively. Additionally, IDH1 R132H, MGMT promoter methylation, progression free survival (PFS), and overall survival (OS) were also collected retrospectively. Data was combined with that of Vaios et al. and Ho et al. Kaplan-Meier analysis and multivariate testing were performed. RESULTS Leukopenia is associated with increased overall survival (p = 0.008) and progression free status (p = 0.02). Grade 3 thrombocytopenia is associated with decreased PFS (p = 0.0005) and OS (p = 0.0006). Grade 1 &amp; 2 lymphopenia is associated with increased progression free survival (p = 0.01 and p = 0.03). Lower baseline absolute lymphocyte count is associated with improved OS (p = 0.007). Higher baseline absolute neutrophil count is associated with worse OS (p = 0.002). CONCLUSION Cytopenia may serve as a prognostic biomarker for OS and PFS. Leukopenia may reflect adequate temozolomide dosing, anti-tumor activity, or changes in the tumor micro-environment. Peripheral biomarker monitoring may improve prognostic stratification and lead to personalized treatment with improved outcomes.
RADT-16. A RETROSPECTIVE COMPARISON OF OUTCOMES AFTER WHOLE BRAIN RADIOTHERAPY AND RAPID SIMPLE (RAPPLE) TARGETED THERAPY FOR BRAIN METASTASES IN MATCHED COHORTS OF PATIENTS WITH POOR PROGNOSIS
Authors: Alan Nichol, Gurjit Parmar, Tim Kong, Jeremy Hamm, Mitchell Liu, Shilo Lefresne, Hannah Carolan, Eric Berthelet, Jessica Chan
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND For patients whose poor prognosis does not warrant stereotactic radiosurgery, we use the RAPPLE radiotherapy technique to treat multiple brain metastases. RAPPLE uses single-isocenter, coplanar volumetric modulated arc therapy and a non-stereotactic head-shell with IntegraBite™. Brain metastasis are contoured in a single gross tumour volume and expanded by 3 mm to create a planning target volume, covered by 95-110% of 20 Gy in 5 fractions. Our study compares clinical outcomes after RAPPLE and whole brain radiotherapy (WBRT). METHODS From January 2017 to December 2021, we identified patients receiving a first course of RAPPLE and matched patients receiving a first course of WBRT. Cox regression was used to analyze overall survival and Fine-Gray analysis was used to analyze intracranial progression. For each cohort, we compared patient-reported fatigue before and 2-6 weeks after radiotherapy. RESULTS Each cohort had 137 patients whose median Karnofsky Performance Score was 70. The diagnoses were lung cancer (72%) and other cancers (28%). The median survival was 4.1 months for RAPPLE and 4.2 months for WBRT (log-rank p = 0.8). On multivariable analysis of survival, the radiotherapy technique was not predictive (HR = 0.96, 95%CI: 0.73-1.25, p = 0.7). On multivariable analysis, intracranial progression was more likely after RAPPLE (HR = 1.6, 95%CI: 1.1 – 2.3, p = 0.02). The 18-month risk of intracranial progression was 0.49 for RAPPLE and 0.37 for WBRT (p = 0.04). After RAPPLE, 17% of patients required more focal RT and 4% required salvage WBRT, while after WBRT, 3% required focal RT and 4% required repeat WBRT. After RAPPLE, mean patient-reported fatigue remained stable from baseline to first follow-up (2.18 vs. 2.27, p = 0.9), but after WBRT it worsened (1.95 vs. 2.63, p = 0.002). CONCLUSIONS Ninety-six percent of patients treated with RAPPLE avoided WBRT. Patients reported worse fatigue after WBRT.
NIMG-03. IMPACT OF CONCURRENT IMMUNOTHERAPY AND STEREOTACTIC RADIOSURGERY ON METASTATIC BRAIN DISEASE: A THREE-DIMENSIONAL MAGNETIC RESONANCE FINGERPRINTING RADIOMIC ANALYSIS
Authors: Shearwood McClelland III, Sree Gongala, Tiffany Hodges, Nisha Korakavi, Chris Flask, Dan Ma, Chaitra Badve
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Unlike traditional chemotherapy (limited by the blood-brain barrier), the central nervous system penetrance of immunotherapy allows for synergy with stereotactic radiosurgery (SRS), the standard-of-care management of limited brain metastases. Magnetic resonance fingerprinting (MRF) is a novel technology allowing for simultaneous imaging quantification of multiple tissue properties. We present the first serial MRF results in concomitant SRS/immunotherapy for metastatic brain disease. METHODS A patient with known history of small cell lung cancer (SCLC) presented with a seizure. MRI revealed a solitary 1 cm right occipital metastasis, subsequently receiving SRS rather than whole-brain radiation therapy to optimize cognition preservation. Durvalumab (with carboplatin/etoposide) was given one week before SRS (22 Gy single-fraction). Pre-SRS MRF scans were obtained with the Gamma Knife stereotactic headframe in place. Post-SRS MRF scans were obtained at 1, 3, and 5 months. MRF data was processed and region of interest analysis was performed to measure T1 and T2 values within the lesion using MATLAB. RESULTS The mean T1 and T2 values of the solid tumor (ST) in precontrast MRF maps decreased over time with a slight increase at final follow-up. Specifically, the T1 values decreased from 2131 ms (Pre-SRS) to 1018 ms, then 996 ms followed by a slight increase to 1296 ms. Similarly, the T2 values progressively decreased from 143 ms (Pre-SRS) to 45 ms (first follow-up) to 43 ms (3-month follow-up), with an increase (51 ms) at last follow-up. CONCLUSIONS In this first report of MRF in concomitant immunotherapy/Gamma Knife SRS (and the first in a SCLC patient). MRF demonstrated serial drop in T1 and T2 over time followed by slight increase at 5 months follow-up. The alterations observed in T1 and T2 MRF are compatible with post-treatment effects in the tumor's tissue characteristics, including decreased cellularity, water content, and presence of paramagnetic substances.
NCMP-19. OUTCOMES FOLLOWING PALLIATIVE CEREBROSPINAL FLUID DIVERSION FOR NEOPLASTIC LEPTOMENINGEAL DISEASE: A SYSTEMATIC REVIEW
Authors: Adela Wu, James Zhou, Stephen Skirboll
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Leptomeningeal disease (LMD)—cancer involvement of meninges or disseminated through the cerebrospinal fluid (CSF) system—indicates widespread or advanced cancer. LMD leads to symptomatic hydrocephalus, for which palliative CSF diversion may be indicated. We conducted a systematic review exploring published literature on outcomes of permanent CSF diversion for hydrocephalus among pediatric and adult patients with LMD from primary brain tumor or systemic cancers. METHODS We searched PubMed, Embase, and Web of Science from database inception until 8/20/2022, using search terms including but not limited to ‘cancer’, ‘hydrocephalus’, and ‘shunt’. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were followed. Inclusion criteria were English-language, quantitative studies of patients with LMD and hydrocephalus, with at least five subjects. RESULTS We screened 2440 abstracts and 152 full-text articles to yield a final cohort of 23 articles. The retrospective studies reported outcomes for 2895 patients, among which 995 patients (34.3%) specifically had LMD on presentation. Fourteen studies reported proportions of patients with LMD and hydrocephalus who underwent surgery for permanent CSF diversion (range: 9.9-100%), including endoscopic third ventriculostomy, ventriculoperitoneal or lumboperitoneal shunts. Postoperative complication rates were 0-37.7% with no cases of extraneural metastases via shunt. Rates of symptomatic relief following CSF diversion ranged from 50-100% in studies that reported data. In 14 studies, median overall survival ranged from 2.1-17.1 months. Three studies reported median survival after shunt surgery for LMD (2-3.3 months). CONCLUSION A rare entity with dismal prognosis, LMD and disseminated tumor can present as symptomatic hydrocephalus in patients with cancer. Symptom relief can be achieved with palliative surgery for permanent CSF diversion with relatively low complication rates. Prospective studies are needed to further assess outcomes and needs of this patient population.
CTNI-83. MATRIX REGIMEN FOR NEWLY DIAGNOSED PRIMARY CNS DIFFUSE B-CELL LYMPHOMA
Authors: Richard Green, Ruben Guzman-Marin, Candy Miranda
Journal: Neuro-Oncology (2023)

Abstract We report our experience treating 25 patients with newly diagnosed primary CNS diffuse B-cell lymphoma with the MATRix regimen as reported by Ferreri, et al in 2016. The median age was 66 y (range 30-85); 12 patients were men and 13 were women. Twenty-three had cerebral mass lesions, 1 had a paraspinal mass, and 1 leptomeningeal disease. Treatment consisted of 4 cycles of rituximab 375 mg/sq m (Days 1, 6); methotrexate 3.5 g/sq m (Day 2); cytarabine 2 g/sq m every 12 h (Days 3, 4); and thiotepa 30 mg/sq m (Day 5). Patients without disease progression received carmustine 400 mg/sq m and thiotepa 5 mg/kg followed by autologous bone marrow transplantation. Four patients were switched to MATRix after 6 cycles of methotrexate and rituximab and received only 2 initial cycles including cytarabine and thiotepa. Overall, 18 patients completed initial chemotherapy. Sixteen of these 18 went on to transplantation; one patient had had early disease progression, and in one no stem cells could be collected. Five patients (median 73 y; range 64-85 y) died early after 1-2 cycles. The causes of early death were neutropenic fever, septic thrombophlebitis, and cardiac arrest. One of the 16 patients who completed the entire regimen including transplantation died of fungal pneumonia and the other 15 experienced no serious acute toxicity. One patient had late disease progression and 2 developed symptomatic leukoencephalopathy. Seventeen of the 25 patients remain alive. Median TTP for the cohort is 605 days, and OS 738 days. These preliminary data suggest that the MATRix regimen in safe and highly effective in the newly diagnosed setting. However, the high incidence of early death in patients over 65 y shows that the regimen is too toxic for older individuals.